It is the intent of this proposal to develop a fast CT-based method for minimally invasively quantitating the regional functional characteristics of the intramyocardial microcirculation and its concurrent myocardial function. This method would overcome the limitations of other methods such as the direct, invasive, visualization of, in vivo, epicardial and endocardial microcirculations. Moreover, as the mechanical forces in those surface locations are likely different from those within the wall, our proposed tomographic perfusion imaging approach is more likely to provide data representative of the intramural micrccirculation. Our preliminary data indicate that a unique relationship exists linking the myocardial microcirculatory branching geometry and the parameters derived from the CT-based indicator dilution curve measured in the imaged intact myocardium. As a consequence, our hypothesis is that a myocardial CT-based indicator dilution curve is uniquely related to the patho-physiological behavior of the transmural myocardial microcirculation and can therefore be quantitated with a specificity and sensitivity that is suitable for advancing physiological and clinical investigation of the in vivo myocardial microcirculation. We propose to achieve our goal by a mathematical model of the microcirculation with branching geometry parameters to be derived from direct measurements of the in situ myocardial microcirculation using micro-CT imaging. We will develop and validate this model by three aims: (1) Development of the model will be based on micro-CT imaging of "biopsies" of the myocardium after we have scanned the pigs using fast-CT during an intravenous injection of contrast agent. (2) Validation of the structural aspects of the model will be performed by occlusion of selected vessel diameters by microembolization of the in vivo myocardial microcirculation with non-radioactive microspheres of diameters selected to occlude a known fraction of microvessels and their perfusion territories. (3) Change in local LV wall function (fast CT-based quantitation of rate of wall thickening and index of myocardial oxygen consumption) will be evaluated with controlled pharmacological modulation of the myocardial microcirculation and inotropic state so as to establish relative roles of conduit and exchange microvessels in myocardial performance. The significance of a successful outcome would be detection of an early, microvascular, stage of coronary disease as occurs in atherosclerosis, diabetes mellitus, and hypertension. This tool should also be applicable to other imaging modalities from which tissue indicator dilution curves can be obtained.